Malignant Hyperthermia (MH) is a genetic disease in man and various animal species predisposing to a life-threatening hypermetabolic syndrome that is triggered by certain anesthetic agents. The experiments described in this project are designed to answer questions regarding the etiology and pathophysiology of MH in man. Studies will involve 3 different species (man, dog, pig) each with a genetic predisposition to MH. Comparative studies in the canine and porcine MH genetic models will be performed at varying levels of organization, i.e., purified protein subcellular organelle membrane, intact skeletal muscle tissue and the intact animal. Parallel membrane and muscle tissue levels of investigations will be performed on tissue obtained from human MH diagnostic muscle biopsy specimens. It is expected that comparison of animal and human data will provide a better basis for understanding MH in man. Etiologic studies focus on a hypothesis that MH is a consequence of sustained myoplasmic Ca2+, secondary to the action of anesthetics on Ca2+ regulation by the sarcoplasmic reticulum (SR) membrane system. Various sites of electromechanical (E-C) coupling will be investigated pharmacologically with intact skeletal muscle and biochemically in fragmented SR membrane vesicles and purified protein. The results are expected to determine where in the E-C coupling pathway a defect may occur in MH muscle and if the same defective site(s) is common to the 3 species studied. Such results may contribute to our understanding of mechanisms for other muscle diseases. The clinical syndrome of masseter muscle rigidity, often a symptom of MH onset, is a serious and unresolved problem associated with anesthesia. Experiments designed to study intact animals, biopsied skeletal muscle and isolated SR membranes will attempt to address the uniqueness of masseter muscle pharmacology and physiology in relation to this clinical syndrome. In addition to expanding our knowledge and understanding of the MH syndrome, these studies will also contribute to our understanding of the mechanism of action of volatile anesthetics at different levels of biological organization.